This project investigates the feasibility of treating non-resectable pulmonary cancers by perfusing the lungs in isolation with high concentrations of anticancer agents. A study was initially undertaken to investigate the kinetics of doxorubicin, an anticancer agent active against sarcoma, in in situ perfused dog lungs. The procedure entailed inserting cannulae into the left pulmonary artery and left venous return, effectively isolating the left lobes from the systemic circulation. A wide range of perfusate doxorubicin concentrations was studied in order to determine the rate of drug uptake and retention in the lung tissue. These studies have lead to a Phase I clinical trial utilizing the hemiperfusion technique in metastatic sarcoma patients. The surgical and perfusion procedures were successfully performed in all the patients examined to date. However, in human lung, doxorubicin accumulation was considerably slower than in the dogs. The studies utilizing in situ hemiperfusion of the lungs supported the concept that technique may be useful to treat certain lung cancers. A total lung perfusion technique was then established and the physiological and biochemical effects of this procedure were examined in dogs. Total bypass and lung perfusion (without drug) for up to 60 min produced no surgical complications. Indicator dilution techniques suggested no acute or chronic (up to 8 weeks post-perfusion) damage occurred to the lungs and these results were supported by histopathology of the lung tissue. Studies are presently under way to investigate the kinetics and toxicity of various candidate antitumor agents in the total lung perfusion model.